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Lookup NU author(s): Professor Neil PerkinsORCiD, Dr Renee Johnson
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The NF-kappa B family of transcription factors is a well-established regulator of the immune and inflammatory responses and also plays a key role in other cellular processes, including cell death, proliferation, and migration. Conserved residues in the trans-activation domain of RelA, which can be posttranslationally modified, regulate divergent NF-kappa B functions in response to different cellular stimuli. Using rela-/-mouse embryonic fibroblasts reconstituted with RelA, we find that mutation of the threonine 505 (T505) phospho site to alanine has wide-ranging effects on NF-kappa B function. These include previously described effects on chemotherapeutic drug-induced apoptosis, as well as new roles for this modification in autophagy, cell proliferation, and migration. This last effect was associated with alterations in the actin cytoskeleton and expression of cellular migration-associated genes such as WAVE3 and alpha-actinin 4. We also define a new component of cisplatin-induced, RelA T505-dependent apoptosis, involving induction of NOXA gene expression, an effect explained at least in part through induction of the p53 homologue, p73. Therefore, in contrast to other RelA phosphorylation events, which positively regulate NF-kappa B function, we identified RelA T505 phosphorylation as a negative regulator of its ability to induce diverse cellular processes such as apoptosis, autophagy, proliferation, and migration.
Author(s): Msaki A, Sanchez AM, Koh LF, Barre B, Rocha S, Perkins ND, Johnson RF
Publication type: Article
Publication status: Published
Journal: Molecular Biology of the Cell
Year: 2011
Volume: 22
Issue: 17
Pages: 3032-3040
Print publication date: 07/07/2011
ISSN (print): 1059-1524
ISSN (electronic): 1939-4586
Publisher: American Society for Cell Biology
URL: http://dx.doi.org/10.1091/mbc.E11-04-0280
DOI: 10.1091/mbc.E11-04-0280
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